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Pan-HDAC Inhibitors Promote Tau Aggregation by Increasing the Level of Acetylated Tau

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Pan-HDAC Inhibitors Promote Tau Aggregation by Increasing the Level of Acetylated Tau International Journal of Molecular Sciences Article Pan-HDAC Inhibitors Promote Tau Aggregation by Increasing the Level of Acetylated Tau 1,2, 1,3, 3,4 5 2 Hyeanjeong Jeong y, Seulgi Shin y, Jun-Seok Lee , Soo Hyun Lee , Ja-Hyun Baik , Sungsu Lim 1,* and Yun Kyung Kim 1,3,* 1 Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea 2 Department of Life Sciences, Korea University, Seoul 02841, Korea 3 Division of Bio-Medical Science & Technology, University of Science and Technology (UST), Daejeon 34113, Korea 4 Molecular Recognition Research Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea 5 Center for Biomicrosystems, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea * Correspondence: [email protected] (S.L.); [email protected] (Y.K.K.) These authors contributed equally to this work. y Received: 1 August 2019; Accepted: 29 August 2019; Published: 1 September 2019 Abstract: Epigenetic remodeling via histone acetylation has become a popular therapeutic strategy to treat Alzheimer’s disease (AD). In particular, histone deacetylase (HDAC) inhibitors including M344 and SAHA have been elucidated to be new drug candidates for AD, improving cognitive abilities impaired in AD mouse models. Although emerged as a promising target for AD, most of the HDAC inhibitors are poorly selective and could cause unwanted side effects. Here we show that tau is one of the cytosolic substrates of HDAC and the treatment of HDAC inhibitors such as Scriptaid, M344, BML281, and SAHA could increase the level of acetylated tau, resulting in the activation of tau pathology. Keywords: histone deacetylase inhibitor; tau acetylation; tau aggregation; Alzheimer’s disease 1. Introduction Alzheimer’s disease (AD) is a chronic neurodegenerative disorder that characterized by extracellular deposits of amyloid plaques and neuronal deposits of tau aggregates composed of hyperphosphorylated tau [1,2]. Over the last few decades, a number of compounds, designed to reduce the formation of amyloid plaques or to enhance their clearance, have failed in clinical trials. Since the causes of AD are still unknown, diverse targets are being applied for anti-Alzheimer’s drug discovery. Among the diverse, epigenetic regulation has been proposed to be a new promising therapeutic strategy for neurological disorders, particularly for AD [3]. In aged animal models, decreased levels of histone acetylation have been observed in the hippocampus and cerebral cortex [4,5]. Such changes could contribute to the development of neurodegeneration by down-regulating genes, which are critical for learning and memory. A number of recent studies have showed that histone deacetylase (HDAC) inhibitors exhibit neuro-protective properties, rescuing learning and memory abilities impaired in AD animal models [4,6–11]. Accordingly, HDAC inhibition has emerged as an alternative therapeutic strategy in AD treatment. Histone deacetylases are divided into four classes. Class I, II, and IV contain the classic HDAC enzymes, and Class III contains the sirtuin enzymes, which require NAD+ as a cofactor [12,13]. In 2009, Francis et al. proposed that epigenetic alteration by HDAC inhibition could be a therapeutic target to prevent AD progression [7]. In their study, trichostatin A, a HDAC inhibitor, rescued fear memory Int. J. Mol. Sci. 2019, 20, 4283; doi:10.3390/ijms20174283 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2019, 20, 4283 2 of 12 impaired in APP/PS1 mice by increasing the acetylation of histone H4. In 2010, Peleg et al. reported that SAHA, a HDAC inhibitor, rescued age-dependent memory impairment in old mice by increasing the acetylation of histone H4 [4]. In 2017, Volmar et al. also suggested M344, a HDAC inhibitor, to be a promising drug candidate for AD [6]. In their study, M344 prevented cognitive declines in an AD animal model by down-regulating AD-related genes that contribute to APP processing and tau phosphorylation. Accumulating studies have supported that other HDAC inhibitors including valproic acid, 4-phenylbutyrate, MPT0G211, and nicotinamide presented similar therapeutic effects in AD animal models [8,10,14–16]. However, histone is not the only substrate of HDACs. A variety of non-histone substrates of HDACs exist in nuclei and cytosols [17,18]. Most HDAC inhibitors listed above are poorly selective and could cause unwanted side effects by acetylating non-histone proteins. In fact, several studies have showed that tau is a direct substrate of HDAC. In 2011, Cohen et al. reported that trichostatin A, a pan-HDAC inhibitor, increased tau acetylation [19]. In 2014, Noack et al. also reported that tubastatin A, a HDAC6 inhibitor, increased acetylated tau [20]. Tau is a neuron-specific microtubule-binding protein that stabilizes microtubules [21–23]. When pathologically modified, tau dissociates from microtubules and becomes insoluble aggregates [24–28]. Although hyperphosphorylation has been considered to be the major modification of tau, initiating tau pathology [2,29], recent studies have demonstrated that tau acetylation is also strongly associated with tau pathology [19,30,31]. Elevated levels of acetylated tau have been observed in AD patients [19,30], and acetylated tau has been colocalized with insoluble tau aggregates in the brain of AD animal models [19,32,33]. Biochemical studies have identified that tau acetylation slows down tau turnover, inhibiting proteasomal degradation [20,34]. In a result, acetylated tau accumulates, activating tau aggregation [19,30,34,35] and increased acetylated tau levels in the brain of tau transgenic mouse models are enough to cause an acetylation-mediated tau pathological cascade [32,33]. Due to the pathological implication, tau acetylation should be carefully evaluated in HDAC-targeting drug discovery. In this study, we collected 34 commercially available inhibitors of histone deacetylases (HDACs, SIRTs) and histone acetyl transferases (HATs) and evaluated the effect on tau acetylation and aggregation. Among the tested, pan-HDAC inhibitors (Scriptaid, M344, BML281, and SAHA) markedly induced intracellular tau aggregation. All the selected HDAC inhibitors increased the acetylation of tau at the residue K280 strongly as well as its representative cytosolic and nucleic substrates, tubulin and histone. 2. Results 2.1. Evaluation of HDAC Modulators on Tau-BiFC Sensor For the comprehensive evaluation of HDAC inhibitors, we collected 30 commercially available modulators of histone deacetylases (HDACs, SIRTs), together with 4 modulators of histone acetyl transferases (HATs). Then, the compound effects on tau aggregation were evaluated by using a tau aggregation sensor, named tau-BiFC [36]. As a fluorescence turn-on sensor, tau-BiFC fluorescence turns on only when tau assembles together (Figure1A). Tau-BiFC fluorescence directly represents the level of tau assembly in a cell, from soluble dimers to insoluble aggregates [36–40]. Forskolin was used as a positive control [36,41]. Among tested, 6 HDAC inhibitors, Scriptaid, M344, BML281, SAHA, Trichostatin A, and Fluoro-SAHA, induced tau-BiFC fluorescence noticeably by showing more than 3-fold increase at 3 µM concentration (Figure1B). In particular, Scriptaid, M344, BML281, and SAHA, HDAC inhibitors containing an aliphatic hydroxyamide linker acid, showed the strongest tau-BiFC fluorescence responses (Figures1C and2A). Int. J. Mol. Sci. 2019 , 20 , x FOR PEER REVIEW 3 of 12 evaluate acetylation levels of α-tubulin, a cytoplasmic substrate of HDACs, and histone H3, a nuclear substrate of HDACs [42,43]. The Tau-BiFC High group strikingly elevated both α-tubulin acetylation and histone H3 acetylation. The acetylation levels of α-tubulin increased over 3.0- up to 3.3-fold, and the acetylation levels of histone H3 increased over 3.5- up to 4.3-fold. In comparison, Tau-BiFC Null and Tau-BiFC Low groups did not show noticeable changes in α-tubulin acetylation (Figure 1D,E). In the Tau-BiFC Null group, BML210 and PhenylbutyrateNa slightly increased histone acetylation by showing 2.5- and 2.3-fold increases. The results indicate that Scriptaid, M344, BML281, and SAHA are pan-HDAC inhibitors, which strongly inhibit both cytoplasmic and nuclear HDACs. As a cytosolic substrate of HDACs, tau was also strongly acetylated by pan-HDAC inhibitors. Similar to Int. J.the Mol. increased Sci. 2019, 20 level, 4283 of acetylated tubulin, Tau(K280) acetylation increased almost 3-fold by the 3 of 12 treatment of the pan-HDAC inhibitors. Different from acetylated tubulin, acetylated tau seems accumulated in the cells, increasing the amount of total tau. FigureFigure 1. Evaluation 1. Evaluation of of HDAC HDAC modulators modulators on tau-BiFC tau-BiFC sensor. sensor. (A ()A Illustration) Illustration of tau-BiFC of tau-BiFC cell system. cell system. Tau-BiFCTau-BiFC cell expressescell expresses full-length full-length tau conjugatedtau conjugated with with the non-fluorescent the non-fluorescent N- or N- C-terminal or C-terminal fragments fragments of Venus fluorescence protein. When tau assembles together, Venus fluorescence turns on. of Venus fluorescence protein. When tau assembles together, Venus fluorescence turns on. (B) Screening (B) Screening of 34 compounds in tau-BiFC cells. Tau-BiFC cells were treated with 34 library of 34 compounds in tau-BiFC cells. Tau-BiFC cells were treated with 34 library compounds at 3 µM for 48 h. BiFC fluorescence intensities were quantified
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